The present invention relates to a pharmaceutical composition for use in the treatment of diabetic neuropathy. In particular, the present invention relates to a pharmaceutical composition for use in the treatment of diabetic neuropathy caused by a microvascular circulatory disturbance.
The term "diabetic neuropathy" indicates a neuropathy caused by a chronic hyperglycemic condition. The diabetic neuropathy is roughly classified into groups of multiple neuropathy, autonomic neuropathy and single neuropathy. Diabetic neurosis usually indicates a symmetrical, distal, multiple neuropathy mainly causing sensory disturbance. Both multiple neuropathy and autonomic neuropathy are neuropathies characteristic of diabetics.
A cause for the diabetic neuropathies is a chronic hyperglycemic state. However, the mechanism of the crisis has not been fully elucidated yet. For the crisis mechanism of the neuropathy caused by hyperglycemia, there are two main theories, i.e. vascular dysfunction and disturbed metabolism.
According to the vascular dysfunction theory, the blood flow is disturbed by changes of the blood abnormalities (such as acceleration of platelet aggregation, increase of the blood viscosity and decrease of the red blood-cell deformity) or by changes of the blood vessel abnormalities (such as reduction of the production of nitric oxide from the endothelial cells of blood vessels and acceleration of the reactivity on vasoconstrictive substances), then the hypoxia of nerves is caused, and finally the nerves are degenerated. For example, when the platelet aggregation is accelerated by the chronic hyperglycemic state, the microvascular disturbance is caused to result in diabetic neuropathy.
On the other hand, in the disturbed metabolism theory, the causes thereof can be classified into a group of the activation of the polyol metabolic pathway and the non-enzymatic protein glycosylation, It is commonly accepted that both vascular dysfunction theory and disturbed metabolism theory are correct. Also, it is considered that the disturbed metabolism mainly causes the initial stage of the diabetic neuropathy and, as the disease reaches an advanced stage, the concern of the-vascular dysfunction increases.
Epalrestat [Japanese Patent Unexamined Published Application (hereinafter referred to as "J. P. KOKAI") No. Sho 57-40478; EP 47109A] which is an aldose reductase inhibitor effective in inhibiting the activation of the polyol metabolic pathway is used as a remedy for diabetic neuropathy. However, this remedy is not so effective and is unsatisfactory for curing the human disease, while the symptoms of animals can be almost completely recovered with it. Reasons for this phenomenon are, for example, that the effects of this remedy vary depending on the species and that the amount of the aldose reductase varies among the patients.
Under these circumstances, not only remedies developed on the basis of the disturbed metabolism theory but also remedies developed on the vascular dysfunction theory are being developed. It is known that vasodilators such as .alpha.1 receptor antagonists, angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, calcium channel blockers, endothelin receptor antagonists, prostaglandin preparations and nitric oxide donors inhibit the neuropathy of streptozotocin induced diabetic rats or they even improve the neuropathic symptoms. However, most of these vasodilators have a blood pressure-lowering effect which is undesirable for the patients with diabetic neuropathy.